Cocaine produces increases in blood pressure and heart rate by interfering with the uptake and degradation of norepinephrine at adrenergic nerve terminals. Animal studies in our laboratory suggest that intravenous cocaine produces greater systemic responses in the pregnant than nonpregnant sheep which are accompanied by reduced uterine blood flow and fetal oxygen levels. Our study is based on the hypotheses that: 1) the systemic cardiovascular response to intravenous cocaine is greater during pregnancy than observed in the non-pregnant state. 2) The pregnant uterus, when compared with a parallel vascular bed (hind limb) is a primary target organ for cocaine action. 3) The response of the pregnant uterus to cocaine is mediated by norepinephrine and serotonin receptors. 4) Fetal oxygen utilization is directly affected by cocaine-induced reductions in uterine blood flow. Phase I (maternal) studies will be conducted in the pregnant ewe and repeated two weeks postpartum to contrast the pregnant and nonpregnant response to cocaine. At 100 days of gestation pregnant sheep will undergo arterial and venous catheterization and thoracotomy for placement of a pulmonary artery flow probe for measurement of maternal heart rate, blood pressure, cardiac output and calculation of systemic vascular resistance. In a second surgery ten days later, flow probes will be secured for maternal femoral and uterine blood flow measurements and fetal arterial and venous catheters will be placed for fetal blood pressure, heart rate, and blood gas (p02, 02 content, pC02, pH) levels. Cocaine in graded doses will be randomized and given intravenously or locally into the uterine artery to determine cocaine effects on maternal systemic vascular resistance, uterine and femoral blood flow and vascular resistance. Analysis for maternal and fetal plasma cocaine levels will define distribution and half life in the fetal and maternal compartments. Cocaine administration following complete alpha adrenergic blockade with phenoxybenzamine and serotonergic blockade with Katanserin will help define the mechanism of cocaine induced vasoconstriction in the uterus. Two weeks postpartum the ewes will be retested with cocaine to determine systemic and peripheral vascular response in the non-pregnant state. In Phase II (fetal) studies surgical instrumentation at 110 days will consist of catheters in the maternal femoral artery and vein, fetal umbilical vein and fetal aorta and placement of an electromagnetic flow probe on the fetal common internal iliac artery for umbilical blood flow determinations. From these measurements, fetal-placental cardiovascular function, cocaine accumulation, oxygen delivery to the fetus and fetal oxygen extraction and consumption will be evaluated during single and repetitive maternal or direct fetal cocaine administration. The composite data from this comprehensive study will provide new information on the risks of cocaine use during pregnancy.